One category of pharmaceutical products to be used for cancer treatment is a topoisomerase inhibitor, and examples thereof include camptothecin. Camptothecin is penta cyclic alkaloid, which has been extracted and isolated from Camptotheca acuminata (a plant of China) by Wall et al. (USA) in 1966, and it was found to have a high antineoplastic activity and a wide antineoplastic spectrum (Non-patent Document 1). A conventional cancer chemotherapy agent exerts an antineoplastic activity by topoisomerase II inhibition, while camptothecin inhibits an enzyme function of topoisomerase that plays a role in DNA replication, repair, gene recombination, and transcription by topoisomerase I inhibition.
Camptothecin has some problems in use as a drug. Among them, with respect to water insolubility, some water-soluble camptothecin analogues each improved in terms of insolubility have been proposed (see Patent Document 1, for instance). In particular, irinotecan hydrochloride (CPT-11), which is a water-soluble camptothecin derivative and has been put on the market in 1994 in Japan, is a prodrug and exerts a high antineoplastic activity, so that it was highly expected in clinical fields. After administration, irinotecan hydrochloride that is a prodrug is metabolized into SN-38 that is an active metabolite, and it exerts an antineoplastic activity.
Meanwhile, when irinotecan and a salt thereof are administered, severe side effects such as bone marrow dysfunction and gastrointestinal disturbance are caused. Therefore, use thereof is severely restricted. In addition, there is a problem that an antineoplastic activity is decreased by hydrolysis of an α-hydroxylactone ring due to the sensitivity in an aqueous environment, which is unique to camptothecin and an analogue thereof.
In order to solve the above problems and perform the optimum cancer treatment using a camptothecin analogue as the cell cycle-specific antimetabolite, it is necessary to maintain the local concentration of the drug for a long period of time. However, there is a fact that such a drug has a half-life of as short as several hours after intravenous administration or subcutaneous administration. The drug is useful as a release control agent that can be used to deliver a pharmaceutical agent having a therapeutic concentration. One approach for solving these problems, delivering a camptothecin analogue stably and effectively to a target lesion site, and exerting an antineoplastic activity in a target lesion site is to incorporate the drug into a carrier having a closed vesicle form. Some proposals on formation of a liposome formulation including camptothecins have already been made. For example, it has been reported that, when camptothecin is included in a liposome membrane, hydrolysis of an α-hydroxylactone ring is suppressed (see, for instance, Patent Document 2 and Non-patent Document 2). In addition, there has been disclosed a method of causing a liposome membrane to contain SN-38 itself, which is an active main body of irinotecan hydrochloride (Non-patent Documents 3 and 4). However, SN-38 is difficult to stabilize in a liposome membrane and disappears rapidly in blood, so that it is difficult that the concentration of SN-38 in plasma is maintained for a long time.
There has also been reported a manufacturing example based on a customary method in which irinotecan hydrochloride (a water-soluble derivative) is enclosed in a liposome by the passive loading method and is stabilized by fixing it on the membrane of lipid bilayer electrostatically (Non-patent Document 5).
Patent Document 1: JP 3-4077 B
Patent Document 2: JP 9-504517 A
Non-patent Document 1: Am. Chem. Soc., 94 (1966), 388
Non-patent Document 2: Tomas G. Burke et al., Biochemistry, 32 (1993), 5352-5364
Non-patent Document 3: W. Gao et al., J. of Chromatography B, 791 (2003), 85-92
Non-patent Document 4: Joshua Williams et al., J. of Controlled Release, 91 (2003), 167-172
Non-patent Document 5: Yasuyuki Sazuka et al., Cancer Letter 127 (1998), 99-106